Animal parasite-control method using insect growth regulators

ABSTRACT

Methods and formulations for treating animal ectoparasites, effective against parasites such as fleas and ticks are provided. The methods comprise topically co-administering a non-mobile insect growth regulator and a mobile insect growth regulator to the animal. Parasiticidal formulations for treating animal ectoparasites are also provided, which can be safe to use and avoid the many common deleterious side effects of conventional topical formulations. The topical formulations comprise a combination of two insect growth regulators, a non-mobile insect growth regulator and a mobile insect growth regulator. The topical formulation can be packaged with the two insect growth regulators together or packaged to prevent mixing of the two insect growth regulators prior to administering the topical insecticide formulation to the animal.

This application is a continuation of U.S. patent application Ser. No.12/206,648, filed Sep. 8, 2008, currently pending, which claims thebenefit of U.S. Provisional Application No. 60/970,444, filed Sep. 6,2007, and U.S. Provisional Application No. No. 60/970,621, filed Sep. 7,2007, the contents of which are incorporated herein by reference.

BACKGROUND OF INVENTION

This invention relates generally to a method of controlling parasitesand formulating and applying topical formulations that can havesignificant parasiticidal or anti-parasite activity, such as onesuitable to use on house pets such as dogs and cats.

The infestation of companion animals with fleas, ticks, and the like ishighly undesirable and as such, it is beneficial to develop improvedproducts to fight such infestation. Topical applications can bedesirable since many formulations are acceptably safe when usedtopically, even if not when used internally.

Topical applications are more advantageous if the amount of liquidapplied to the animal can be minimized. This should be balanced with theneed for appropriate dosage to achieve the desired pesticidal effect.Therefore, it is desirable to use highly active insecticide so that thetotal volume of the insecticide applied to the animal can be minimized.

Topical applications often contain an insect growth regulator (IGR)component. IGRs kill flea larvae and prevent flea eggs from hatching.Such formulations provide for an effective flea control system sinceonly about 5% of the existing fleas on an animal can be adults and theother 95% in a juvenile state (eggs and larvae). For example,methoprene, hydroprene and pyriproxyfen (commercially available asNylar) are IGRs that prevent flea eggs from hatching.

However, it has been determined that various IGR containing formulationshave drawbacks due the characteristics of the chosen IGR. For some IGRs,it is difficult to maintain an effective concentration at the affectedarea of the animal and requires that a large volume to be applied. Forother IGRs, it is difficult to provide sufficient coverage surroundingthe treatment area, thereby permitting parasites to persist in otherareas of the animal or in the environment such as pet bedding,carpeting, upholstery, and so forth. Again, a large volume is requiredto provide coverage.

This can cause considerable mess and can lead to an unpleasant smell.Additionally, if the dosage of a topical formulation is in a largevolume, it can be easily shaken off by the animal thereby reducing theeffectiveness of the formulation. Furthermore, when the animal is ahouse pet, there is a further complication in that the formulationshould be safe for human contact. A large dose of an IGR may lead tostaining of furniture, carpeting and the like. Finally, even if safe,topical formulations should not be irritating or lead to rashes, hairloss or exhibit other unpleasant side effects.

Accordingly, it is desirable to develop improved formulations.

SUMMARY OF THE INVENTION

Generally speaking, in accordance with the invention, a topicalapplication of two IGRs is provided. It has been determined that thetopical application of two IGRs—preferably an IGR with high mobilityproperty such as methoprene or hydroprene due to its volatility (mobileIGR) and a non-mobile IGR such as pyriproxyfen—on the same animal,especially a non-human animal, so as to be present at the same time,achieves surprising synergistic effect and offers a broader and moreeffective means of infestation control than using the same totalquantity of either IGR separately.

As referred to herein, a mobile IGR is an IGR that exists in liquid formor as a sublimating solid at room temperature under one atmosphericpressure, which is capable of translocation (vaporizing and redepositingfrom one area to another area). Examples of a mobile IGR includemethoprene and hydroprene. A mobile IGR is volatile and capable oftranslocation from one area of the animal to another area of the animalor an area in the environment. As referred to herein, a non-mobile IGRis an IGR that exists in solid form without sublimation at roomtemperature under one atmospheric pressure, which is not capable oftranslocation. An example of a non-mobile IGR is pyriproxyfen. Anon-mobile IGR does not spread or migrate and therefore is capable ofmaintaining a high effective concentration at the location it isapplied.

Due to its increased potency, the application in accordance with theinvention requires less total active ingredients. It can be safe to useand avoids many common deleterious side effects of conventional topicalapplication.

One preferred embodiment of the invention provides a topical formulationthat contains a combination of either methoprene or hydroprene withpyriproxyfen and at least one additional insecticide capable ofproviding insecticidal activity on the adult insect (“adulticide”). Theselection of the combination of insecticides and insect growthregulators produces a composition having high parasitical activity,thereby providing broad protection against a variety of parasites with asingle application of the topical formulation. The use of two selectedIGRs has also been determined to lead to a synergistic effect, such asimproved activity per total volume ratios. The treatment method usingsuch a formulation can also be useful to improve the speed of result anddecrease the reoccurrence, compared to other formulations.

As used herein, the identification of an active ingredient, e.g.,pyriproxyfen, is intended to also refer to other pharmaceutically activeforms of the active ingredient, such as esters, salts, hydrochlorides,acid or base forms, isomers and so forth.

Thus, an advantage of the invention is to provide a topical applicationmethod for controlling parasites.

Another advantage of the invention is to provide an improved method ofparasite control application more rapidly and/or more permanently thanother topical formulations.

Another advantage of the invention is to provide an improved method ofparasite control application using less active ingredients than othertopical formulations.

Other objects, advantages and features will be in part apparent and inpart pointed out.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In accordance with one preferred embodiment of the invention, a methodof animal parasite control is provided which involves a combination ofmethoprene (or hydroprene), pyriproxyfen and an adulticide that iseffective against parasites such as fleas, flea eggs, and otherpotential targets. This combination of active ingredients can produce atopical formulation that provides broad protection against parasites.

Preferably, the treatment of different parasites can be targeted byincluding a particular adulticide including, but not limited to,macrocyclic lactones, natural pyrethrins, synthetic pyrethroids,Etofenprox, neo-nicotinoids, phenylpyrazoles, or combinations thereof.The adulticide or combination of adulticides should be present in anamount effective to control parasites in the adult state, preferablybetween 1% and 90% of the total administration.

The IGRs should be present in an amount effective to control parasitesin the juvenile state. The amount of pyriproxyfen is preferably between0.005% and 5% of the total administration. The amount of methoprene (orhydroprene) is preferably between 0.01% and 10% of the totaladministration. In a preferred embodiment of the invention, the ratio ofmethoprene to pyriproxyfen is in the range of 20:1 to 1:20 by weight.

It should be understood that the application of methoprene (orhydroprene), pyriproxyfen and an adulticide can be, without limit to anyspecific ordering of the application. Thus, it is possible to applymethoprene (or hydroprene), pyriproxyfen, and the adulticide in a singlecombined formulation or in succession and achieve desirable benefits.

In one preferred embodiment of the invention, the insecticidecomposition of the invention can be packaged in a single dose package.Single dose containers make storage, use, and disposal more convenientfor animal owners.

In another preferred embodiment of the invention, the two IGRs and theadulticide can be packaged in a container having two associated,preferably attached, but individual, separated chambers to prevent themixing of these ingredients prior to the administration to reducecross-reactivity and improve the shelf-life and efficacy of aformulation where the adulticide needs to be separated from methopreneand pyriproxyfen. Prior to administration, the packages containing thefirst and second formulations in their respective separate chambers areopened, and the first and second formulations are dispensedsimultaneously or at least at about the same time to the animal.

In another preferred embodiment of the invention, the IGRs and theadulticide is applied to the surrounding of the animal, such as a petbed or a carpet.

In another preferred embodiment of the invention, the IGRs and theadulticide is prepared in liquid form with a carrier including 1% to 70%aerosol propellants.

In another preferred embodiment of the invention, the IGRs and theadulticide is prepared in liquid form to be dispensed to surfaces viapump spray.

It is understood that the active ingredients need not be mixed togetherprior to administration of the topical formulation to the animal, butmay be stored in suitable carriers separately. Suitable carriers for theIGRs and the adulticide include, but are not limited to, vegetable oils,surfactants, glycols, esters, light petroleum, aldehydes, lactones,triglycerides, amides, silicone polyether copolymers, dialkyl fatty acidamides, pyrrolidones, aqueous dispersions, water, and combinationsthereof. The carrier is preferably N,N dialkyl fatty acid amide, andmost preferably N,N dimethyl octanamide. The carriers should be presentbetween 1% to 99% of the total weight of the composition.

Because compositions in accordance with preferred embodiments of theinvention can be formulated with a relatively high concentration ofactive ingredients, a relatively small application of a spot or line onthe animal can effectively prevent and control parasite infestation onthe animal for approximately one, two and even four or more weekspost-administration.

In the preparation of a formulation for use on animals, there areseveral parameters that should be considered. These are:

-   -   (a) Concentration high enough to minimize the volume of the        topical applied to the animal (one would not want to put 20 ml,        e.g., onto a small dog).    -   (b) Concentration low enough to achieve effective translocation        of the topical insecticide over the animal's skin.    -   (c) The formulation should be stable for six months at 40° F.        and 75% relative humidity, room temperature and −10° F. This        helps ensure that the formulation remains stable under the        conditions that it could meet in commerce.    -   (d) Safe to use on the intended animal—particularly        non-irritating to at least the intended animal, since the        product is applied to the skin. Also safe if ingested by the        animal; ingestion can occur when pets groom themselves.    -   (e) Safe to use by the consumer.    -   (f) Efficacious in use—should kill greater than 90% of the fleas        and ticks up to 28 days.    -   (g) Efficacy would be reduced if crystallization occurred in the        package.    -   (h) Needs to be aesthetically pleasing—“no oily drop” on the        animal when applied.    -   (i) Fast drying to reduce the chance of the animal shaking off        the liquid thereby reducing efficacy.    -   (j) Microbiologically stable.

The proposed mechanism of synergy is not to be construed as limiting inany way. However, it is believed that methoprene and hydroprene arevolatile, with high mobility and therefore capable of migratingthroughout an infested area. It is believed that pyriproxyfen possesseslong-term chemical stability and potency. Thus, a combination of themigratory property of a mobile IGR such as methoprene or hydroprene withthe efficacy of pyriproxyfen achieves increased parasiticidal activitymultiplicatively, rather than offering mere additive results.

It can be advantageous to co-administer additional components toincrease the efficacy and to reduce the irritation of insecticides tothe skin of animals. The formulation can advantageously containspreading agents such as n-octyl pyrrolidone anddioctylsulfosuccinimide, fragrances, and/or antioxidants. Otheradditives to the insecticidal composition include but are not limited tofragrances, surfactants and spreading agents to increase performancesuch as polyoxyethylene (20) sorbitan monolaurate (commerciallyavailable as polysorbate 20 or Tween® 20) and polyoxyethylene (20)sorbitan monooleate (commercially available as polysorbate 80 or Tween®80), and isopropyl myristate. Polymers such as agar, gelatin, alginate,and cationic polymers such as cationic guar, cationic cellulose,cationic acrylates, and polyoxymethylene urea may also be added toprovide enrobing of the insecticide to improve safety and adhesion toskin and hair.

In practice, an effective amount of the insecticidal compositions asdescribed herein may be applied to a companion animal, preferably a dogor a cat, as a foaming shampoo, dip, aerosol spray, pump spray, powder,lotion, emulsifiable concentrate, aqueous or liquid flowable, slowrelease collar, suspension concentrate, powder, and by any other methodssuitable for administering topical compositions to animals.

It will thus be seen that the objects set forth above, among those madeapparent from the preceding description, are efficiently attained and,since certain changes may be made in carrying out the above method andin the composition set forth without departing from the spirit and scopeof the invention, it is intended that all matter contained in the abovedescription shall be interpreted as illustrative and not in a limitingsense.

The following examples of formulations containing two IGRs and oneadulticide active ingredients are given for purposes of illustrationonly and are not intended to be construed in a limiting manner.

Example 1

A Formulation I consistent with an embodiment of the invention isprepared by mixing 0.1% pyriproxyfen, 3.0% methoprene or hydroprene, 40%Etofenprox and 56.9% diisopropyl adipate (DIPA) carrier by weight.

Example 2

A Formulation II consistent with an embodiment of the invention isprepared by mixing 0.05% pyriproxyfen, 10.0% methoprene or hydroprene,85% phenothrin and 4.95% DIPA carrier by weight.

Example 3

A Formulation III consistent with an embodiment of the invention isprepared by mixing 5.0% pyriproxyfen, 0.1% methoprene or hydroprene, 10%fipronil and 84.9% DIPA carrier by weight.

While there have been shown, described and pointed out novel features ofthe present invention as applied to preferred embodiments thereof, itwill be understood that various omissions and substitutions and changesin the form and details of the disclosed invention may be made by thoseskilled in the art without departing from the spirit of the invention.It is the intention, therefore, to be limited only as indicated by thescope of the claims appended hereto.

It is also to be understood that the following claims are intended tocover all of the generic and specific features of the invention hereindescribed and all statements of the scope of the invention which, as amatter of language, might be said to fall therebetween.

1. An insecticidal formulation comprising an effective amount of amobile insect growth regulator component comprising methoprene orhydroprene, which is capable of translocating from one area to anotherarea by vaporizing and redepositing, and a non-mobile insect growthregulator component comprising pyriproxyfen, sufficient to reduce theparasitic infestation of a non-human animal treated with theformulation.
 2. The insecticidal formulation of claim 1, wherein theamount of methoprene or hydroprene is between 0.01% and 10% by weight ofthe total formulation.
 3. The insecticidal formulation of claim 1,wherein the amount of pyriproxyfen is between 0.005% and 5% by weight ofthe total formulation.
 4. The insecticidal formulation of claim 1,wherein a weight ratio of methoprene or hydroprene to pyriproxyfen is inthe range of 20:1 to 1:20.
 5. The insecticidal formulation of claim 1,wherein the mobile insect growth regulator component comprisesmethoprene.
 6. The insecticidal formulation of claim 1, wherein themobile insect growth regulator component comprises hydroprene.
 7. Theinsecticidal formulation of claim 1, further comprising 1% to 99% byweight of a carrier.
 8. The insecticidal formulation of claim 7, whereinthe carrier is an N,N dialkyl fatty acid amide.
 9. The insecticidalformulation of claim 7, wherein the carrier is N,N dimethyl octanamide.10. The insecticidal formulation of claim 7, wherein the carrier isdiisopropyl adipate (DIPA).
 11. The insecticidal formulation of claim 1,further comprising n-octyl pyrrolidone.
 12. The insecticidal formulationof claim 1, wherein mobile insect growth regulator component and thenon-mobile insect growth regulator component are packaged to preventtheir mixing prior to administration, and to permit their dispensingsimultaneously or nearly simultaneously onto the animal.
 13. A method oftreating parasitic infestation in a non-human animal, the methodcomprising topically administering to the animal the insecticidalformulation of claim
 1. 14. The method of claim 13, comprising topicallyadministering to the animal the insecticidal formulation of claim
 2. 15.A method of treating parasitic infestation in a non-human animal, themethod comprising topically co-administering to the animal a mobileinsect growth regulator component comprising methoprene or hydroprene,which is capable of translocating from one area to another area byvaporizing and redepositing, and a non-mobile insect growth regulatorcomponent comprising pyriproxyfen.
 16. The method of claim 15, whereinthe amount of methoprene or hydroprene is between 0.01% and 10% byweight of the total administration.
 17. The method of claim 15, whereinthe amount of pyriproxyfen is between 0.005% and 5% by weight of thetotal administration.
 18. The method of claim 15, wherein the mobileinsect growth regulator component comprises methoprene.
 19. The methodof claim 15, wherein the mobile insect growth regulator componentcomprises hydroprene.
 20. The method of claim 15, wherein the mobileinsect growth regulator component and the non-mobile insect growthregulator component are applied to the animal in a single combinedformulation.
 21. The method of claim 15, wherein the mobile insectgrowth regulator component and the non-mobile insect growth regulatorcomponent are separated to prevent mixing prior to administration, andare dispensed simultaneously or nearly simultaneously onto the animal.22. The method of claim 15, further comprising applying the mobileinsect growth regulator component and the non-mobile insect growthregulator component to a surface in the animal's surroundings.